Introduction

Uses for Lisdexamfetamine Dimesylate

Attention-Deficit/Hyperactivity Disorder

Used as adjunct to psychological, educational, social, and other remedial measures in the treatment of attention-deficit/hyperactivity disorder (ADHD) (hyperkinetic disorder, hyperkinetic syndrome of childhood, minimal brain dysfunction).1367828

Safety and efficacy established in children ≥6 years of age, adolescents, and adults who met criteria for ADHD.234293044454648

Almost all studies comparing behavioral therapy versus stimulants alone show a much stronger therapeutic effect from stimulants than from behavioral therapy, and stimulants (e.g., amphetamines, methylphenidate) remain the drugs of choice for the management of ADHD.5671011121314151617181920

Drug therapy not indicated in all patients with ADHD; consider such therapy only after performing a complete evaluation including medical history.61718

Base use on age, adequate diagnosis (based on medical, special psychological, educational, social resources), and the clinician’s assessment of the severity, duration, and frequency of symptoms and not solely on one or more behavioral characteristics.5617

Binge-Eating Disorder

Used for treatment of moderate to severe binge-eating disorder in adults.4048 Reduces mean number of binge days per week compared with placebo.4048

Do not use for weight loss; use of other sympathomimetic drugs for weight loss associated with serious adverse cardiovascular events.48 Efficacy and safety of lisdexamfetamine for treatment of obesity not established.48

Lisdexamfetamine Dimesylate Dosage and Administration

General

Assess patients for presence of cardiac disease prior to initiation of therapy.48 (See Sudden Death and Serious Cardiovascular Events under Cautions.)

Assess potential for abuse of CNS stimulants prior to initiation of therapy.48 After prescribing amphetamine therapy, carefully maintain prescription records, and educate patients about abuse of stimulants; monitor for signs of abuse and overdose.48 Reevaluate need for continued therapy.48

Administration

Oral Administration

Administer capsules or chewable tablets once daily in the morning without regard to meals.148 Because of potential for insomnia, avoid administering in the afternoon.12830

Alternatively, capsule may be opened and entire contents mixed with water, orange juice, or yogurt until completely dispersed; administer resulting mixture immediately.148 Do not store mixture for use at later time.148

Do not subdivide capsule contents; do not administer a dose less than the entire contents of one capsule or one chewable tablet.148

Warnings/Precautions

Warnings

Abuse Potential

Potential for abuse and dependence.48 Assess risk of abuse prior to initiation of lisdexamfetamine and monitor patients for signs of abuse and dependence during therapy.48 (See Boxed Warning.)

Consider the possibility that family members may abuse the patient’s medication.5

Other Warnings and Precautions

Sudden Death and Serious Cardiovascular Events

Sudden unexplained death, stroke, and MI reported in adults with ADHD receiving usual dosages of stimulants; sudden death also reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of the drugs.19 Postmarketing experience with lisdexamfetamine includes reports of cardiomyopathy, chest pain.48

Although an initial epidemiologic study showed association between use of stimulants and sudden unexplained death in healthy children and adolescents,313233 subsequent large epidemiologic studies in children and young adults or in adults 25–64 years of age found no association between ADHD drug use (stimulants, atomoxetine, pemoline [no longer commercially available in US]) and serious cardiovascular events (MI, stroke, sudden cardiac death), although small increases in cardiovascular risk could not be excluded.35363738

Thoroughly review medical history (including evaluation for family history of sudden death or ventricular arrhythmia) and perform physical examination in all children, adolescents, and adults being considered for stimulant therapy; if initial findings suggest presence of cardiac disease, perform further cardiac evaluation (e.g., ECG, echocardiogram).156

Effects on BP and Heart Rate

Possible modest increases in average BP (i.e., by about 2–4 mm Hg) and heart rate (i.e., by about 3–6 bpm); larger increases may occur.128 Monitor all patients for changes in BP and heart rate.148

Exacerbation or Precipitation of Psychotic Symptoms

May exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorder.15

Psychotic symptoms (e.g., hallucinations, delusional thinking) may occur with usual dosages in children and adolescents without prior history of psychotic illness.16 If psychotic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.16

Precipitation of Manic Symptoms

May precipitate mixed or manic episodes in patients with bipolar disorder.148 Prior to initiating therapy, carefully screen patients for risk factors for developing a manic episode; with screening, include a detailed psychiatric history (e.g., comorbid depressive symptoms or history of depressive symptoms; family history of suicide, bipolar disorder, or depression).148

Manic symptoms may occur with usual dosages in children and adolescents without prior history of mania.1 If manic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.1

Growth Suppression

Long-term (i.e., >12 months) administration expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents.16 Dose-related weight loss reported in children and adolescents during 4 weeks of therapy with lisdexamfetamine.148

Manufacturer recommends monitoring growth during treatment; patients not growing or gaining weight as expected may require temporary discontinuance of treatment.162848 However, AAP states that studies of stimulants in children found little or no decrease in expected height, with any decrease in growth early in treatment being compensated for later on.7

Peripheral Vascular Effects

Peripheral vascular disorders (e.g., Raynaud's phenomenon) reported in patients in all age groups receiving stimulants at therapeutic dosages and at various times throughout treatment course.48 Manifestations usually intermittent and mild, but ulceration of digits and/or breakdown of soft tissue occur rarely.48 Carefully observe patients for digital changes.48 (See Advice to Patients.)

Improvement generally observed following dosage reduction or drug discontinuance; some patients may require further evaluation (e.g., referral to rheumatologist).48

In animals, no effects on embryofetal morphology or survival when lisdexamfetamine administered throughout organogenesis.48 Prenatal and postnatal studies not conducted specifically with lisdexamfetamine.48 Administration of amphetamine to pregnant rats during gestation and lactation resulted in decreased pup survival and body weight correlating with developmental delays at clinically relevant dosages of amphetamine.48

Lactation

Distributed into milk.2548 No reports of adverse effects on nursing infants.2548 Large dosages of dextroamphetamine may interfere with milk production, especially in women whose lactation is not well established.48 Because of potential for serious adverse effects to lisdexamfetamine in nursing infants, breast-feeding not recommended during therapy.48

Pediatric Use

ADHD: Safety and efficacy not established in children <6 years of age.48

Binge-eating disorder: Safety and efficacy not established in pediatric patients <18 years of age.48

Psychotic (e.g., hallucinations, delusional thinking) or manic symptoms reported in children and adolescents receiving stimulants for management of ADHD.148 (See Warnings under Cautions.)

Sudden death reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants.148

Long-term administration expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents.1 (See Growth Suppression under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.48 Differences not identified with other reported clinical experience in responses between geriatric and younger adults.48

Interactions for Lisdexamfetamine Dimesylate

Amphetamines and their derivatives are metabolized by CYP2D6 and may show mild inhibition of CYP2D6 metabolism.48 The prodrug lisdexamfetamine not metabolized by CYP isoenzymes before its conversion to dextroamphetamine.48

No clinically important interactions shown with lisdexamfetamine and substrates of CYP1A2, 2D6, or 3A; potential for minimal inhibition of CYP2C19.41 Dosage adjustment of concomitantly administered substrates of these isoenzymes not necessary.48

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Potential pharmacokinetic interaction (increased exposure to dextroamphetamine); may increase risk of serotonin syndrome.48 Consider alternative therapy with a non-serotonergic drug or drug that does not inhibit CYP2D6.48

Use concomitantly only when potential benefit justifies the potential risk.48 If clinically warranted, use lower dosages of lisdexamfetamine during initiation of therapy.48 Monitor patients for signs and symptoms of serotonin syndrome, especially when therapy is initiated or dosage increased.48

If serotonin syndrome occurs, discontinue lisdexamfetamine, the CYP2D6 inhibitor, and any concomitantly administered serotonergic agents.48 (See Specific Drugs, Tests, and Foods under Interactions and also see Serotonin Syndrome under Cautions.)

Serotonergic Drugs

Use concomitantly only when potential benefit justifies the potential risk.48 If clinically warranted, use lower dosages of lisdexamfetamine during initiation of therapy.48 Monitor patients for signs and symptoms of serotonin syndrome, especially when therapy is initiated or dosage increased.48

If serotonin syndrome occurs, discontinue lisdexamfetamine and the concomitant serotonergic drug(s).48 (See Specific Drugs, Tests, and Foods under Interactions and also see Serotonin Syndrome under Cautions.)

Enhanced activity of tricyclic antidepressants; desipramine or protriptyline may cause striking and sustained increases in dextroamphetamine concentrations in the brain; cardiovascular effects can be potentiated48

Use concomitantly only if potential benefit justifies potential risk48

Lisdexamfetamine Dimesylate Pharmacokinetics

Absorption

Bioavailability

Lisdexamfetamine (a prodrug of dextroamphetamine) is rapidly absorbed from the GI tract.128 Peak plasma concentrations of lisdexamfetamine occur in approximately 1 hour; concentrations are low and transient; nonquantifiable by 8 hours after administration.1 Peak plasma concentrations of dextroamphetamine occur in approximately 3.5–3.7 hours.1330

Onset

Duration

Food

Food (high-fat meal or yogurt) delays time to peak plasma concentration of dextroamphetamine by about 1 hour, but administration with high-fat meal, yogurt, or orange juice does not affect magnitude of peak plasma concentration or AUC of dextroamphetamine.148

Distribution

Extent

Amphetamines readily cross the blood-brain barrier and are distributed into most body tissues.26

Amphetamines are distributed into milk in concentrations 3–7 times maternal blood concentrations.2125

Elimination

Metabolism

Lisdexamfetamine (a prodrug of dextroamphetamine) is converted to l-lysine and dextroamphetamine mainly via hydrolytic activity of RBCs, which have high capacity for this metabolism.148

Stability

Storage

Oral

Capsules, Chewable Tablets

Actions

Lisdexamfetamine is a prodrug of dextroamphetamine; dextroamphetamine may block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneural space.1232830

Pharmacologic actions of amphetamines are qualitatively similar to those of ephedrine and include CNS and respiratory stimulation and sympathomimetic activity including pressor response, bronchodilation, and contraction of the urinary bladder sphincter.2324

Theories of dysfunction in ADHD focus on the prefrontal cortex, which controls many executive functions (e.g., planning, impulse control).5 Stimulants have putative effects on central dopamine and norepinephrine pathways that are crucial in frontal lobe function.5

Produces an anorexigenic effect, leading to loss of weight.1523 No primary effect on appetite demonstrated in humans; postulated that anorexigenic effects are secondary to increased sympathetic activity resulting from release of norepinephrine and dopamine.22

Advice to Patients

Importance of providing patient or caregiver with a copy of the manufacturer’s patient information (medication guide); discuss and answer questions about its contents as needed.1 Importance of advising patient or caregiver to read and understand contents of medication guide before initiating therapy and each time the prescription is refilled.1

Importance of informing patients that lisdexamfetamine is a controlled substance possibly leading to abuse and dependence.48 Advise patients on proper storage and disposal of controlled substances.48

Risk of increased BP and heart rate; importance of advising patients to monitor BP and heart rate during therapy.48

Risk of psychiatric effects (e.g., psychosis, mania), even in patients without history of such effects.48

Risk of weight loss or delayed growth rate; importance of monitoring height and weight of pediatric patients during therapy.48

Appetite suppression may occur.15 Giving morning dose with a meal and providing high-caloric drink or snack late in the evening when stimulant effects have subsided may be helpful.5

Importance of instructing patients about the potential for amphetamines to impair their ability to perform potentially hazardous activities, such as driving or operating heavy machinery.1

Potential risk of peripheral vascular disorders (e.g., Raynaud's phenomenon) and associated signs and symptoms (e.g., numbness, coolness, pain, or changes in color [from pale to blue to red] in fingers or toes).48 Advise patients to report any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes and to immediately inform clinician if any signs of unexplained wounds appear on fingers or toes; further clinical evaluation may be appropriate.48

5. American Academy of Child and Adolescent Psychiatry. Practice parameter for the use of stimulant medications in the treatment of children, adolescents and adults. Washington, DC; 2001. From the AACAP website. Accessed 2007 Aug 15. http://www.aacap.org/galleries/PracticeParameters/StimMed.pdf

6. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with attention deficit hyperactivity disorder. Washington, DC; 2007. From the AACAP website. Accessed 2007 Aug 15. http://www.aacap.org/galleries/PracticeParameters/New_ADHD_Parameter.pdf